The instant invention relates to a process for the preparation of erythromycin derivatives, or pharmaceutically acceptable salts thereof, which contain an optionally substituted propargyl group at the 6-O-position.
Macrolide antibacterial agents are widely used to treat and prevent bacterial infections. However, the discovery of bacterial strains which have resistance or insufficient susceptibility to these agents has promoted development of compounds with modified or improved profiles of antibiotic activity.
Commonly owned U.S. Pat. No. 5,866,549 and commonly owned pending U.S. application Ser. No. 09/273,140, filed Mar. 19, 1999, teach the small scale syntheses of 6-O-propargyl erythromycin derivatives. Large scale production of the same, however, requires a process which avoids complicating factors such as chromatography of intermediates and low-yielding steps, i.e., problems usually associated with macrolide or ketolide synthesis due to the number of reactive groups on the molecule.
Therefore, there is still a continuing need for more efficient and cleaner syntheses of 6-O-propargyl erythromycin derivatives.
In one embodiment of the instant invention, therefore, is disclosed a process for preparing 6-O-propargyl erythromycin derivatives, or a pharmaceutically acceptable salts thereof, comprising the steps of
(a) simultaneously reacting a compound of formula (I) 
wherein
L1 is selected from the group consisting of halo, trifluoromethanesulfonyl, and optionally substituted phenylsulfonyl; and
R1 is hydrogen or optionally substituted heteroaryl, a compound of formula (II) 
xe2x80x83wherein
R2 and R3 are taken together and are selected from the group consisting of xe2x95x90Nxe2x80x94Oxe2x80x94R6, xe2x95x90Nxe2x80x94Oxe2x80x94C(O)xe2x80x94R6, xe2x95x90Nxe2x80x94Oxe2x80x94C(R7a)(R7b)xe2x80x94OR8, xe2x95x90Nxe2x80x94Oxe2x80x94Si(R9)3, xe2x95x90Nxe2x80x94N(R10a)(R10b), and xe2x95x90Nxe2x80x94Nxe2x95x90C(R11a)(R11b);
R4 and R5 are independently hydrogen or a hydroxyl protecting group;
R6 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
R7a and R7b are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
R8 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl; or
R7a and R7b together or R7a and R7b together are alkylene; each R9 is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl;
R10a and R10b are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, and a nitrogen-protecting group; or
R10a and R10b together are alkylene; and
R11a and R11b are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, and phenylalkyl; or
R11a and R11b together are alkylene, and an alkoxide base to provide a compound of formula (III) 
a preferred embodiment of which are compounds of formula (III-a) 
and
a particularly preferred embodiment of which are compounds of formula (III-b) 
Compounds of formula (III) are useful as intermediates in the synthesis of 6-O-propargyl erythromycin derivatives of formula (IV) 
a preferred embodiment of which are compounds of formula (IV-a) 
Another embodiment of the instant invention, therefore, comprises the step of
(a) reacting the compound of formula (III) with a first acid and sodium nitrite at a pressure of about 15 psi to about 70 psi to provide the compound of formula (IV).
Compounds of formula (IV) are useful as intermediates in the synthesis of 6-O-propargyl erythromycin derivatives of formula (V) 
a preferred embodiment of which are compounds of formula (V-a) 
and
compounds of formula (V-b) 
wherein
R1a is optionally substituted heteroaryl,
and
a particularly preferred embodiment of which are compounds of formula (V-c) 
Another embodiment of the instant invention, therefore, comprises the steps of
(a) reacting the compound of formula (IV-a) with 1,1xe2x80x2-carbonyldiimidazole and a first base, followed by treatment of the product with ammonia or ammonium hydroxide and a second base to provide the compound of formula (V-a); and
(b) optionally reacting the product of step (a) with a compound of formula L1xe2x80x94R1a, a palladium catalyst, an additive, and the first base, to provide the compound of formula (V-b).
Compounds of formulas (V) are useful as intermediates in the synthesis of 6-O-propargyl erythromycin derivatives of formula (VII) 
preferred embodiments of which are compounds of formula (VII-a) 
compounds of formula (VII-b), 
and
compounds of formula (VII-c) 
and
a particularly preferred embodiment of which are compounds of formula (VII-d) 
Another embodiment of the instant invention, therefore, comprises the steps of
(a) reacting the compound of formula (V) with a second acid to provide a compound of formula (VI) 
a particularly preferred embodiment of which are compounds of formula (VI-a) 
(b) reacting the product of step (a) with an oxidizing agent to provide the compound of formula (VII);
(c) optionally reacting the product of step (b) with the compound of formula L1xe2x80x94R1a, the palladium catalyst, the additive, and the first base; and
(d) optionally deprotecting the product of step (b) or step (c) to provide the compound of formula (VII-c).
In a particularly preferred embodiment of the instant invention, L1xe2x80x94R1a is 2-(5-bromo-2-thienyl)pyridine.
Another embodiment of the instant invention, therefore, comprises the step of
(a) reacting 2-(2-thienyl)pyridine and N-bromosuccinimide.
The instant invention discloses a method for the synthesis of 6-O-propargyl erythromycin derivatives. As used in the specification, the following have the meanings indicated.
The term xe2x80x9cadditive,xe2x80x9d as used herein, refers to monodentate phosphorus-containing ligands of formulas P(RC)3 (phosphines) and P(ORD)3 (phosphites), wherein each RC is independently hydrogen; alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho-tolyl; and optionally substitted heteroaryl such as furyl and pyridyl; and wherein each RD is independently alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho-tolyl; and optionally substituted heteroaryl such as furyl and pyridyl. Specific examples of these additives include tri(alkyl)phosphines such as trimethylphosphine, triethylphosphine, tributylphosphine, and the like; tri(cycloalkyl)phosphines such as tricyclopropylphosphine, tricyclohexylphosphine, and the like; tri(aryl)phosphines such as triphenylphosphine, trinaphthylphosphine, and the like; tri(heteroaryl)phosphines such as tri(fury-2-yl)phosphine, tri(pyrid-3-yl)phosphine, and the like; tri(alkyl)phosphites such as trimethylphosphite, triethylphosphite, tributylphosphite, and the like; tri(cycloalkyl)-phosphites such as tricyclopropylphosphite, tricyclohexylphosphite, and the like; tri(aryl)phosphites such as triphenylphosphite, trinaphthylphosphite, and the like; and tri(heteroaryl)phosphites such as tri(fury-2-yljphosphite, tri(pyrid-3-yl)phosphite, and the like. The term xe2x80x9cadditive,xe2x80x9d as used herein, also refers to bidentate phosphines such as 1,4-bis(diphenylphosphino)butane (dppb), 1,2-bis(diphenyl-phosphino)ethane (dppe), 1,1-bis(diphenylphosphino)methane (dppm), 1,2-bis(dimethyl-phosphino)ethane (dmpe), 1,1xe2x80x2-bis(diphenylphosphino)ferrocene (dppf), and the like.
The term xe2x80x9calkoxide base,xe2x80x9d as as used herein, refers to (M)+(OR1)xe2x88x92, wherein (M)+ is a cation selected from the group consisting of lithium, sodium, and potassium, and R1 is alkyl, as defined herein. Examples of alkoxide bases include lithium methoxide, lithium ethoxide, lithium iso-propoxide, lithium tert-butoxide sodium methoxide, sodium ethoxide, sodium iso-propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium iso-propoxide, potassium tert-butoxide, and the like.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a saturated, monovalent straight or branched chain hydrocarbon having from one to six carbons. Examples of alkyls are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and the like.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, attached to the parent molecular group through a sulfonyl, as defined herein.
The term xe2x80x9calkylene,xe2x80x9d as used herein, refers to a divalent straight or branched chain saturated hydrocarbon diradical having from one to six carbons. Examples of alkylenes are ethylene, propylene, butylene, pentylene, hexylene, and the like.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a monovalent straight or branched chain hydrocarbon group having from two to six carbons and at least one carbon-carbon triple bond.
The term xe2x80x9camino,xe2x80x9d as used herein, refers to xe2x80x94NH2 or a derivative formed by independent replacement of one or both hydrogen atoms thereof with a substituent or substituents independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, and an amino protecting group.
The term xe2x80x9caminosulfonyl,xe2x80x9d as used herein, refers to an amino group, as defined herein, attached to the parent molecular group through a sulfonyl group, as defined herein.
The terms xe2x80x9camino protecting group,xe2x80x9d or xe2x80x9cnitrogen protecting group,xe2x80x9d as used herein, refer to selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures. Examples of amino protecting groups include methoxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl (Cbz), chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-butoxycarbonyl (Boc), para-methoxybenzyloxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triphenylsilyl, and the like. Preferred nitrogen protecting groups of the instant invention are benzyloxycarbonyl (Cbz) and tert-butoxycarbonyl (Boc).
The term xe2x80x9caprotic solvent,xe2x80x9d as used herein, refers to solvents in which the starting materials and products are at least partially soluble and which does not donate protons during reactions in which it is not used as a reagent. Examples of aprotic solvents include, C2-C5 alkylamides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, and the like; C4-C6 dialkoxyalkyls such as DME, 1,2-diethoxyethane, and the like; C3-C10 ketones such as acetone, 2-butanone; 3-pentanone, 2-butanone, 2-pentanone, 2,5-heptanedione, tert-butyl methyl ether, and the like; optionally substituted C1-C7 hydrocarbons such as pentane, hexane, heptane, nitromethane, acetonitrile, and the like; optionally substituted aromatic hydrocarbons such as benzene, toluene, 1,4-dichlorobenzene, nitrobenzene, and the like; ethers such as diethyl ether, diisopropyl ether, and the like; and esters such as ethyl acetate isopropyl acetate, and the like.
The term xe2x80x9cazido,xe2x80x9d as used herein, refers to xe2x80x94N3.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to xe2x80x94C(O)xe2x80x94.
The term xe2x80x9ccarboxamido,xe2x80x9d as used herein, refers to an amide; for example, an amino group, as defined herein, attached to the parent molecular group through a carbonyl group, as defined herein.
The term xe2x80x9ccarboxyl,xe2x80x9d as used herein, refers to xe2x80x94CO2H or a derivative formed by replacement of the hydrogen atom thereof by a carboxyl protecting group.
The term xe2x80x9ccarboxyl protecting group,xe2x80x9d as used herein, refers to selectively introducible and removable groups which protect carboxyl groups against undesirable side reactions during synthetic procedures and includes all conventional carboxyl protecting groups. Examples of carboxyl groups include methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), para-nitrobenzyl, para-methoxybenzyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2-trichloroethyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, arylalkoxyalkyl benzyloxymethyl 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, and the like. Preferred carboxyl protecting groups of the instant invention are alkyl and arylalkyl.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to xe2x80x94CN.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a monovalent saturated cyclic hydrocarbon group having from three to seven carbons.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.
The terms xe2x80x9cfirst acidxe2x80x9d and xe2x80x9csecond acid,xe2x80x9d as used herein, refer to reagents capable of donating protons during the course of a chemical reaction. Examples of acids include mineral acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, and the like; organic acids such as formic, acetic, propionic, trifluoroacetic, and the like; and sulfonic acids such as methanesulfonic, para-toluenesulfonic, para-bromosulfonic, para-nitrosulfonic, and the like. The acid chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
The terms xe2x80x9cfirst basexe2x80x9d and xe2x80x9csecond base,xe2x80x9d as used herein, refer to reagents capable of accepting protons during the course of a chemical reaction. Examples of first and second bases include carbonates such as lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and the like; phosphates such as potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, and the like; trialkylamines such as triethylamine, diisopropylethylamine, and the like; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like; anionic nitrogen bases such as lithium bis(trimethylsilylamide), sodium bis(trimethylsilylamide), potassium bis(trimethylsilylamide), lithium diisopropylamide (LDA), and the like; and bicyclic amines such as DBN, DBU, and the like. The base chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
The term xe2x80x9chalo,xe2x80x9d as used herein refers to F, Cl, Br, or I.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, refers to cyclic, aromatic five- and six-membered groups, wherein at least one atom is selected from the group consisting of nitrogen, oxygen, and sulfur, and the remaining atoms are carbon. The five-membered rings have two double bonds, and the six-membered rings have three double bonds. Heteroaryls of the instant invention are exemplified by fliranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, triazinyl, and the like. The heteroaryl groups of the instant invention are connected to the parent molecular group through a carbon atom in the heteroaryl ring. The heteroaryl groups of the instant invention can be optionally substituted with one, two, or three radicals independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxy, cyano, halo, hydroxyl, nitro, perfluoroalkyl, perfluoroalkoxy, thioalkoxy, phenyl, and a second heteroaryl group selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, and triazinyl. The phenyl and heteroaryl groups substituting the heteroaryl groups of the instant invention are attached to the parent heteroaryl group through either a covalent bond, an alkyl group, an oxygen, or a carbonyl group. The phenyl and heteroaryl groups attached to the parent heteroaryl groups of the instant invention can also be further substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy. The heteroaryl groups of the instant invention can also be fused to a phenyl ring, in which case the heteroaryl group can be connected to the parent molecular group through either the heteroaryl part or the phenyl part of the fused ring system. Heteroaryl groups of this type are exemplified by quinolinyl, isoquinolinyl, benzofuranyl, indolyl, and the like.
The term xe2x80x9chydroxyl,xe2x80x9d as used herein, refers to xe2x80x94OH or a derivative formed by replacement of the hydrogen atom thereof with a hydroxyl protecting group.
The term xe2x80x9chydroxyl protecting group,xe2x80x9d as used herein, refers to selectively introducible and removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures. Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl methoxymethyl, methylthiomethyl, benzyloxymeihyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxyl protecting groups for the instant invention are acetyl (Ac or xe2x80x94C(O)CH3), benzoyl (Bn or xe2x80x94C(O)C6H5), and trimethylsilyl (TMS or xe2x80x94Si(CH3)3).
The tero xe2x80x9coxidizing agent,xe2x80x9d as used herein, refers to reagents useful for oxidizing the 3-hydroxyl of the macrolide ring to the 3-carbonyl. Preferred oxidizing agents are N-chlorosuccinimide-dimethyl sulfide (Corey-Kim) or carbodiimide-DMSO (modified Swern).
The term xe2x80x9cpalladium catalyst,xe2x80x9d as used herein, refers to optionally supported palladium(0) such as palladium metal, palladium on carbon, palladium on acidic, basic, or neutral alumina, and the like; palladium(0) complexes such as tetrakis(triphenylphosphine)palladium(0); palladium(II) salts such as palladium acetate or palladium chloride; and palladium(II) complexes such as allylpalladium(II) chloride dimer, (1,1xe2x80x2-bis(diphenylphosphino)ferrocene)-dichloropalladium(II), bis(acetato)bis(triphenylphosphine)palladium(II), and bis(acetonitrile)dichloropalladium(II).
The term xe2x80x9cperfluoroalkoxy,xe2x80x9d as used herein, refers to a perfluoroalkyl group attached to the parent group through an oxygen atom.
The term xe2x80x9cperfluoroalkyl,xe2x80x9d as used herein, refers to an alkyl group in which all of the hydrogen atoms have been replaced with fluoride atoms.
The term xe2x80x9cpharmaceutically acceptable salt,xe2x80x9d as used herein, refers to salts or zwitterionic forms of the compounds of the instant invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, amino groups in the compounds of the instant invantion can be quaternized with as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulphuric, and phosphoric and organic acids such as oxalic, maleic, succinic, and citric.
Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts cations based on lithium, sodium, potassium, calcium, magnesium, and aluminum and nontoxic quaternary ammonia and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibernzylphenethylamine, 1-ephenamine, and N,Nxe2x80x2-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
The term xe2x80x9cphenyl,xe2x80x9d as used herein, refers to a six-membered, aromatic, carbocyclic group. The phenyl groups of the instant invention can be optionally substituted by one, two, three, four, or five radicals independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonyl, amino, aminosulfonyl, azido, carboxamido, carboxy, cyano, halo, hydroxyl, nitro, perfluoroalkyl, perfluoroalkoxy, thioalkoxy, another phenyl group, and a heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The phenyl group and the heteroaryl groups which are attached to the parent phenyl group are attached through either a covalent bond, an alkyl group, an oxygen atom, or a carbonyl group. The phenyl and heteroaryl groups optionally substituting the parent phenyl groups of the instant invention can also be further substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, carboxyl, azido, carboxaldehyde, halo, hydroxyl, perfluoroalkyl, and perfluoroalkoxy.
The term xe2x80x9cphenylalkyl,xe2x80x9d as used herein, refers to an phenyl group, as defined herein, attached to the parent molecular group through an alkyl group, as defined herein.
The term xe2x80x9cphenylsulfonyl,xe2x80x9d as used herein, refers to a phenyl group, as defined herein, attached to the parent molecular group through a sulfonyl, as defined herein.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to xe2x80x94SO2xe2x80x94.
The terms xe2x80x9ctreatedxe2x80x9d or xe2x80x9ctreatment,xe2x80x9d as used below, refer to contacting, mixing, diluting, or reacting one or more chemical entities by a reasonable and usual manner in which chemicals are combined. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (xe2x88x9210xc2x0 C. to 250xc2x0 C., typically xe2x88x9278xc2x0 C. to 150xc2x0 C., more typically xe2x88x9278xc2x0 C. to 100xc2x0 C., still more typically 0xc2x0 C. to 100xc2x0 C.), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive reactions) are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for xe2x80x9ctreatingxe2x80x9d in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
Numerous asymmetric centers exist in the compounds of the instant invention. The instant invention contemplates stereoisomers and mixtures thereof. Individual stereoisomers of compounds are prepared by synthesis from starting materials containing the chiral centers. These starting materials are either commercially available or are made by the methods described hereinbelow and resolved by techniques well-known in the art.
Percentages obtained by HPLC analyses of starting materials and products were calculated from the the area under the curve (AUC).
All of the processes of this invention can be conducted as continuous processes. The term xe2x80x9ccontinuous process,xe2x80x9d as used herein, refers to the conduction of a reaction to provide an intermediate followed by use, optionally in situ, of the intermediate, without isolation, in a subsequent reaction. The term xe2x80x9cin situ,xe2x80x9d as used herein, refers to use of an intermediate in the solvent or solvents in which the intermediate was prepared without removal of the solvent.
The instant invention will be better understood in connection with Schemes 1-8. It will be readily apparent to one of ordinary skill in the art that the process of the instant invention can be practiced by substitution of the appropriate reactants and that the order of the steps themselves can be varied.
Erythromycins can be protected as 9-oximes as described in U.S. Pat. Nos. 4,990,602; 4,990,602; 4,331,803; 4,680,386; and 4,670,549. Preferred oximes are those wherein R and R together are O-(1-isopropoxycyclohexylketal)oxime. Reaction of erythromycin A with hydroxylamine and formic acid in methanol provides an erythromycin A 9-oxime derivative which can be further derivatized without isolation. The preferred amount of hydroxylamine is about 7 to about 10 molar equivalents per molar equivalent of erythromycin A. From about 2 to about 5 molar equivalents of formic acid are used for each molear equivalent of erythromycin A.
Erythromycins can also be protected as C-9 hydrazones (as described in U.S. Pat. No. 5,929,219) by applying chemistry described in J. Am. Chem. Soc., 78, 388-395, (1956). The erythromycin C-9 hydrazones are prepared by reacting the erythromycin with an optionally substituted hydrazine in an alcohol for about 12 to about 36 hours. The C-9 hydrazone erythromycin can further be reacted with nitrogen protecting group precursors by the methods described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3rd edition, John Wiley and Sons, New York, Chapter 7, (1999). For example, the nitrogen of the C-9 hydrazone erythromycin can be protected by treatment of the former with a silylating agent such as triisopropylsilyl triflate and a base base such as triethylamine in a solvent such as dichloroethane to provide 9-(N-triisopropylsilyl)hydrazone erythromycin derivatives.
Erythromycin 9-hydrazones can be converted to an azines by methods described in U.S. Pat. No. 3,780,020 and German Patent 1,966,310. For example, the hydrazone can be treated with the appropriate ketone, aldehyde or orthoformate, optionally with a cosolvent, and optionally with a dehydrating agent such as molecular sieves. The reaction is conducted at a temperature between room temperature and the boiling point of the ketone, aldehyde, or co-solvent for about 1 to about 24 hours. The azine nitrogen can be further protected by treatment with the appropriate ketal in the presence of catalytic formic or acetic acid at ambient temperature for about 18 hours.
The 2xe2x80x2- and 4xe2x80x3-hydroxyl groups of each of the aformentioned erythromycin derivatives can be protected sequentially or simultaneously by reaction with a suitable hydroxyl protecting group precursor in an aprotic solvent as described in U.S. Pat. No. 5,892,008. Typical hydroxyl-protecting reagents include acetylating agents and silylating agents such as acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, and trialkylsilyl chlorides. For the unisolated erythromycin A 9-oxime described above, it is preferred that the benzoylation is carried out with benzoic anhydride, optionally with base, in THF, optionally with isopropyl acetate, to provide the protected erythromycin A 9-oxime. For the other erythromycin derivatives described above, benzoylation of the hydroxyl group is typically accomplished by treatment of the erythromycin 9-oxime derivative with a benzoylating reagent such as benzoic anhydride.
Once protected, the erythromycin derivatives can be further derivatized by the chemistry described below. 
As shown in Scheme 1, conversion of compounds of formula (II) to compounds of formula (III) by simultaneous treatment of the former over about 3 to about 3.5 hours with optionally substituted propargyl chlorides, bromides, iodides, triflates, or sulfonates in the presence of a base such as lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, and potassium tert-butoxide, preferably potassium tert-butoxide. Preferred solvents used for this conversion are aprotic solvents such as DMSO, diethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, mixtures thereof, or mixtures of one of these solvents with ether, tetrahydrofuran, 1,2-dimethxyethane, or acetonitrile. In a preferred embodiment, the solvent used for this conversion is a mixture of DMSO and THF. The reaction is preferably conducted at about 0xc2x0 C. to about 5xc2x0 C. for about 3 to about 3.5 hours. 
As shown in Scheme 2, conversion of compounds of formula (III) to compounds of formula (IV) can be accomplished by treatment of the former with nitrous acid formed in situ by the reaction of sodium nitrite with acids such as HCl, H2SO4, or TFA at pressures between about 15 psi to about 70 psi in solvents comprising a mixture of water and an alcohol such as methanol, ethanol, propanol, isopropanol, or tert-butanol, preferably ethanol. The deoximation is preferably accomplished with hydrochloric acid present in about 5 to about 10 molar equivalents (preferably about 8) per molar equivalent of the compound of formula (III) and the sodium nitrite present in about 5 to about 8 molar equivalents (preferably 7.5) per molar equivalent of the compound of formula (III). The reaction is preferably conducted at about 20xc2x0 C. to about 40xc2x0 C. for about 2.5 hours to about 16 hours. The pressure of the reaction can be attained by in situ formation of nitrous acid from the reaction of sodium nitrite with acid, or alternatively introduction of N2O4 directly into the system. 
As shown in Scheme 3, conversion of compounds of formula (IV) to compounds of formula (V) can be accomplished by (a) treatment of the former with an excess of base such as sodium hydride, sodium bis(trimethylsilyl)amide, DBU, imidazole, and the like, in the presence of carbonyldiimidazole followed by (b) treatment of the intermediate formed in step (a) with ammonia or ammonium hydroxide in the presence of a base such as potassium tert-butoxide. Step (a) is typically conducted in a mixture of DMF and THF for about 8 to about 24 hours at temperatures between about xe2x88x9230xc2x0 C. to about room temperature. Step (b) is typically conducted in THF at temperatures of about 0xc2x0 C. to about 20xc2x0 C. Portions of this reaction sequence follow procedures described in J. Org. Chem., 1988, 53, 2340. 
As shown in Scheme 4, compounds of formula (V-a) can be converted to compounds of formula (V-b) by treatment of the former with compounds of formula L1xe2x80x94R1a, a palladium catalyst, an additive and a first base. L1 represents any number of covalent bond precursors such as halides (preferably bromide or iodide), trifluoromethanesulfonate, and sulfonate, and R1a represents optionally substituted heteroaryl. Examples of palladium catalysts include optionally supported palladium(0), palladium(0) complexes, palladium(II) salts, and palladium(II) complexes (preferably palladium(II) acetate); examples of additives include monodentate phosphorus-containing ligands and bidentate phosphines (preferably triphenylphosphine); and examples of bases include trialkylamines, heterocyclic amines, and bicyclic amines (preferably triethylamine). The coupling reactions are conducted in aprotic solvents such as DMF, DMSO, DME, acetonitrile THF, or mixtures thereof at temperatures from about room temperature to about 150xc2x0 C., depending on the coupling method chosen and the nature of L1. A thorough survey of coupling procedures, reagents, and solvents for transition metal-catalyzed couplings is provided in xe2x80x9cComprehensive Organic Transformations. A Guide to Functional Group Preparations,xe2x80x9d VCH Publishers, New York (1989), and references therein. 
As shown in Scheme 5, compounds of formula (V) can be converted to compounds of formula (VI) by treatment of the former with mild aqueous acid or by enzymatic hydrolysis to remove the cladinose moiety from the 3-hydroxy group. Representative acids include dilute hydrochloric acid, sulfuric acid, acetic acid, chloroacetic acid, dichloroacetic acid, or trifluoroacetic acid. Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol, acetone, and mixtures thereof. Reaction times are typically about 0.5 to about 24 hours. The preferred reaction temperature is about 5xc2x0 C. to about 60xc2x0 C., depending on the method chosen.
The conversion of compounds of formula (VI) to compounds of formula (VII) can be accomplished by treatment of the former with an N-chlorosuccinimide-dimethyl sulfide complex (Corey-Kim) or a carbodiimide-DMSO complex (modified Swern). In a preferred method, the reactions are conducted in a chlorinated solvent such as dichloromethane or chloroform at about xe2x88x9210xc2x0 C. to about 25xc2x0 C. 
As shown in Scheme 6, conversion of compounds of formula (VII-a) to compounds of formula (VII-b) can be achieved by treatment of the former with the reagents and under the conditions described for the conversion of compounds of formula (V-a) to compounds of formula (V-b) as described in Scheme 4. 
As shown in Scheme 7, removal of the protecting groups on the cladinose groups of compounds of formulas (VII-a) and (VII-b) to provide compounds of formula (VII-c) can be achieved by treatment of the former with methanol at temperatures between 0xc2x0 C. and reflux. Reaction times are typically about 0.5 to about 24 hours, depending on the temperature. 
The preparation of a particularly preferred embodiment of the compound of formula L1xe2x80x94R1a a is shown in Scheme 8. Bromination of 2-(2-thienyl)pyridine to provide 2-(5-bromo-2-thienyl)pyridine can be achieved by treatment of the former with bromine or N-bromosuccinimide (preferably the latter) in the presence of a catalyst such as hydrobromic or methanesulfonic acid in a solvent such as acetic acid, dichloromethane, chloroform, tert-butyl methyl ether, or mixtures thereof (preferably tert-butyl methyl ether). The reaction is typically conducted between 20xc2x0 C. and 50xc2x0 C., and the reaction times are typically about 0.5 to about 24 hours.